WO2022072099A9 - Formes posologiques à libération immédiate, procédés de fabrication et d'utilisation de celles-ci - Google Patents

Formes posologiques à libération immédiate, procédés de fabrication et d'utilisation de celles-ci Download PDF

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Publication number
WO2022072099A9
WO2022072099A9 PCT/US2021/048184 US2021048184W WO2022072099A9 WO 2022072099 A9 WO2022072099 A9 WO 2022072099A9 US 2021048184 W US2021048184 W US 2021048184W WO 2022072099 A9 WO2022072099 A9 WO 2022072099A9
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Prior art keywords
formulation
cellulose
starch
pellets
optional
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PCT/US2021/048184
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English (en)
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WO2022072099A1 (fr
Inventor
Lochlann Pauric CARNEY
Praful Balavant Deshpande
John Gerard O'BRIEN
Jose' VELADA
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Eirgen Pharma, Ltd
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Publication of WO2022072099A1 publication Critical patent/WO2022072099A1/fr
Publication of WO2022072099A9 publication Critical patent/WO2022072099A9/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the disclosure relates generally to dosage forms of active pharmaceutical ingredients, c.g. temozolomide, including forms suitable for pharmaceutical and veterinary' use, and methods of making and using the same.
  • the present invention addresses this need by using pelletising technology, such as extrusion-spheronization, along with a particular ratio of suitable excipients and an active such as temozolomide to provide immediate release capsules or oral dosage forms.
  • the pelletising technology may also be utilized to create immediate release formulations of other suitable active pharmaceutical ingredients.
  • the present invention meets this need by providing a suitable formulation of temozolomide to administer to dogs having such hemangiosarcomas.
  • a pellet formulation comprising a suitable acti vc ingredient, optionally temozolomide or other suitable ami-cancer medication or combination thereof, and a combination of pharmaceutically acceptable excipients.
  • the formulation is an immediate release formulation for real use.
  • a nano/microparticle formulation comprising temozolomide, optionally an additional active pharmaceutical ingredient, and a combination of pharmaceutically acceptable excipients, in embodiments, the nano/micropaniclc formulation can provide immediate release of temozolomide, e.g. by using a blend of excipients.
  • the method can be a method of making an immediate release pharmaceutical formulation, comprising compounding an active pharmaceutical ingredient such as temozolomide with at least one excipient selected from foe group consisting of spheronizing aids (diluents), humectants, stabilizers, binders, superdisintegrants, lubricants, solvents and optional coatings.
  • an active pharmaceutical ingredient such as temozolomide
  • excipients selected from foe group consisting of spheronizing aids (diluents), humectants, stabilizers, binders, superdisintegrants, lubricants, solvents and optional coatings.
  • Another aspect of the disclosure herein is a method for improving batch to batch consistency in an in vitro release profile of an immediate release formulation, the method comprising compounding the active pharmaceutical ingredient with a combination of at least one excipient selected from the group consisting of diluents, binders, supcrdisintcgrants, lubricants, stabilizers, solvents and optional coatings.
  • the invention further comprises a process which comprises blending an API, a diluent/spheronizing aid and a superdisintegrant and dispensing such materials and, adding binders, optional humectants and granulating/wet massing unite ⁇ certain conditions and endpoints; extruding the wet mass; sphcronizing the screened extrudate; drying; fractionizing; adding lubricant and optionally coating to form a formulation having a uniform size and shape suitable for filling capsules, sachets and/or stick packs.
  • the API is selected from temozolomide or similar potent, toxic cytotoxic agent in a high dose load.
  • Another aspect of the disclosure herein is a method of treating a disease or condition comprising administering a formulation or dosage form according to the disclosure herein to a subject in need thereof.
  • the subject is a mammal, including humans and animals such as dogs.
  • the formulations are suitable for young subjects including pediatric patients.
  • FIG. 1 shows dissolution release profiles of tcraozoiomide-loaded pellets according to the disclosure herein.
  • Embodiments of the present invention can meet these needs and provide a range of Immediate release dosage forms as well as improved processes to make such formulations and dosage forms.
  • These formulations may be made bioequivalent to a commercially approved immediate release dosage forms but are also amenable to providing distinct in vitro extended release dissolution profiles and in vivo bioavailability. They can be made suitable for both pediatric patient populations as well as adult patient populations and for veterinary use in animals.
  • immediate release formulations including formulations suitable for delivery to pediatric patients in need of treatment thereof. Such formulations can also be useful in the treatment of adults in need of treatment thereof, e.g. for adult diseases and conditions. Such formulations arc also suitable for veterinary use.
  • the formulations and formulation strategies described herein can be used to provide formulations bioequivalent to a commercially approved immediate release drug products but in a form also deliverable to pediatric patients or to veterinary subjects.
  • Such forms are inclusive of conventional capsules, “easy to open” capsules or sachets that can be administered by emptying the entire contents into a small amount of liquid or onto a small amount of soft food.
  • the immediate release formulations comprise an active pharmaceutical ingredient and an excipient.
  • such immediate release formulations are in the form of spheronized pellets or multiparticulates.
  • the formulations comprise spheronized pellets comprising a suitable blend of excipients utilized in a process to make spheronized pellets, said process comprising ( 1 ) blending API, diluent, superdisintegrant and a spheronizing aid to form a dispensible mass (2) granulating said dispensible mass to form an extradable formulation; (3) extruding; spheronizing; drying; and fractionating the extruded, spheronized, dried mass to form uniform pellets which are optionally lubricated and coated to form pellets suitable for use as described herein.
  • the formulation can he a nano/micro particle formulations, e.g. made by emulsion followed by spray drying/freeze drying, such as an emulsicmi-diffusion-spray/drying freeze (hying technique described herein.
  • the formulations can be a powder formulation, e.g. made by spray congealing.
  • the formulation can be an immediate release coated seed.
  • the formulation can be an active-containing granule.
  • spheromzing aids and diluents arc selected from the group consisting of niicrocryslalline cellulose, anhydrous lactose sugar alcohols, saccharides, polysaccharides, cellulose and cellulose derivatives, starch and starch derivatives, metal silicates, metal phosphates, ionic metal salts, saccharose, glucose, starch, microfine cellulose, mannitol, sorbitol, calcium hydrogen phosphate, aluminum silicate, amorphous silica, sodium chloride, starch, and dibasic calcium phosphate dihydrate); humectams are selected from the group consisting of sorbitol Glycerin, Propylene glycol, Triacctin ; stabilizers selected from the group consisting of tartaric acid and other typically utilized carboxylic acids ; binders selected from the group consisting of polyvinylpyrrolidone, HPMC, Starch, copovidone, guns ; lubric acid,
  • the formulations contemplated and disclosed herein can be bioequivalent to approved immediate release drugs by providing a mean AUCo1 ⁇ 2r following oral dosing to humans in the fasted state which is 80% to 125% of the mean A UCW following oral dosing in the ihsted slate of the approved immediate release drug product.
  • die formulation can be bioequivalent to approved immediate release drug products by providing a mean AUCW following oral dosing to humans in the fasted state which is 80% to 120% of the mean AUCO-M following oral dosing in the fasted state of the approved immediate release drug product.
  • the formulations have the excipients and active in the percentages (wv'wt) as shown in Table l.
  • the formulation can optionally include one or more additional functional additives, including but not. limited to release modifiers (including pore formers), absorption enhancers, fillers (also referred to as diluents), binders (including dry binders), spheronizing aids, flavorants, and lubricants.
  • release modifiers including pore formers
  • absorption enhancers including pore formers
  • fillers also referred to as diluents
  • binders including dry binders
  • spheronizing aids including flavorants, and lubricants.
  • the composition can optionally include an absorption enhancer.
  • absorption enhancers include, but are not limited to, caprylocaproyl macrogolglycerides such as polyethylene glycosylated glycerides, also known as polyglycolized glycerides or PEGylated glycerides.
  • PEGylated glycerides which may be employed in the composition include, but are not limited to, mixtures of monoglycerides, diglycerides, and triglycerides and monoesters and diesters of polyethylene glycol, polyethylene glycosylated almond glycerides, polyethylene glycosylated com glycerides, «id polyethylene glycosylated caprylic/capric triglyceride.
  • the absorption enhancer can have an HLB value from 11 to 18, or 13 to 18, or from 13 to 16, or from 13 to 15, or 11-12.
  • GELUCfRE Globalstar Chemical Company, Paramus, New Jersey, USA
  • GELUC!RE is a well-known excipient which belongs to a family of fatty acid esters of glycerol and PEG esters, also known as polyglycolized glycerides.
  • GELUCIRE is used in various applications including preparing extended release pharmaceutical compositions.
  • GELUCIRE compounds are inert, semi-solid waxy materials which arc amphiphilic and are available with varying physical characteristics such as melting point, HLB, and solubilities in various solvents.
  • lubricants are known in the art mid can include, but are not limited to, stearic acid, magnesium stearate, calcium stearate, aluminum stearate, talc, and siliconized talc.
  • the lubricant is stearic acid.
  • a small amount of lubricants can often be used, e.g. in a range of about 0.1 wt.% to about 5 wL%, or about 0.5 wt% to about 3 wi.%, for example 0.5 wt.%, 0.7 wt.%, 1 wl.%, 1.5 wt.%, or 2 wt.%.
  • the top coat can optionally include a lubricant, e.g. talc.
  • a suitable EC top coat material is commercially available under the trade name SURELEASE, sold as an aqueous, emulsi fied dispersion of plasticized EC.
  • a suitable hypromellose pore former can have a 2% solution viscosity at 20 "C of about 3 cP, a methoxyi % in a range of about 19 to about 30, or about 19 to about 24, or about 25 to about 35, or about 28 to 30, ami a hydroxypropyl % of about 5 to about 15, or about 7 to about 12.
  • the hypromellose can be one commercially available as OPADRY or OPADRY 11 AMB.
  • Immediate release nano/microparticles can be prepared using an emulsion-difiuston-spray diymg/frcezc-drytng technique. With a poorly water-soluble API a single-emulsion technique is more desirable.
  • cold nitrogen gas can be circulated through a column or other vessel while a hot melt mixture of lipid, API, and optional surfactant is sprayed into the column to create a fine mist of particles.
  • the particles can optionally be coated with a up coat of extended release polymer and pore former.
  • the active-containing formulation can be prepared in any suitable form.
  • the drug- containing formulation can make up the entire dosage form, or it can be a region of the dosage form, e.g. as a core or as a coating (for example on an inert seed core, such as a nonpareil).
  • the formulation is in particle form, and optionally top coated.
  • the particles can take any size or shape, e.g. pellets or mini tablets, hi another type of embodiment, active -containing immediate release particles (optionally coated), are filled into a capsule shell, pouch, or sachet, yielding a multiparticulate dosage form.
  • Multiparticulates dosage forms made of multiple particulate units, e.g.
  • Functional coating excipients can be selected from cellulosios, HPMC, ethylcellulosc, waxes, glyceryl monostearate, acrylic polymers (including Eudragits), and combinations thereof.
  • Seal coating excipients can be selected from ce!lulostcs, e.g. HPMC.
  • Pore formers can be selected from cellufosics, HPMC, and lactose.
  • Plasticizers can be used in die seal, functional, and aesthetic coatings, and can be selected from dibutyl sebacate, triethyl citrate, and PEGs, for example.
  • Aesthetic coating materials can be selected from hypromel!ose, polyvinyl alcohol, and commercial coating products such as Opadry3 ⁇ 4? coating. The coatings can be applied as aqueous or non-aqueous solutions.
  • the final dosage form can have any desired amount of active pharmaceutical compound in a unit dose.
  • a capsule shell can be filled with sufficient formulation material, such as granule, particle, or pellet, to yield a dosage form having an amount of drug in a suitable active range.
  • Dosage forms other than capsules e.g. sachets, stick-packs, pills, or tablets, can have the same or similar strengths.
  • Dosage forms, including granules, pellets, sachets, capsules, etc. can be stored with a desiccant.
  • a formulation according to die disclosure- herein can be made to create a unique or customized release dissolution profiles.
  • a formulation according to the disclosure herein can also be made to have consistent unit dose to unit dose in vitro dissolution profiles with limited intra batch variability, or batch-io-batch variability.
  • the dissolution profile can be measured using USP Apparatus 1 (Baskets) at 100 RPM, with a medium of de-aerated purified water, 37 * 0.5 ® C, with a volume of 900 mL.
  • Such processes include aqueous-based extrusion/spheronization to produce granules/pellets suitable for immediate release formulations containing a suitable active ingredient (c.g. temozolomide), coating processes to coat seeds or active-containing granules.
  • a suitable active ingredient c.g. temozolomide
  • One embodiment of a process to make suitable pediatric temozolomide formulation or veterinary formulation wherein the active is temozolomide includes aqueous-based extrusion/spheronization to form multiparticulate granules/pellets which can be uncoated or coated.
  • the preferred immediate release formulations are shown in Table 1.
  • blended capsules suitable for use in preparing such granules can be selected from, for example, Eudragit RL PO. Eudragit RS PO, EC, L-HPC, LH-31, Compritol 888 ATO and Koliidon SR.
  • other excipients including binders andtor absorption enhancers, lipidic agents, diluents, spheronisring aids, flavoring agents and pore formers may be utilized in the aqueous-based extruded granule formulation.
  • pellets are readily made from the extrudablc aqueous-based formulation without the need for additional coating(s) to achieve a target in vitro and in vivo profile.
  • Such a process can include (l) forming an aqueous-based extrudablc mass including active and inactive excipients; (2) extruding such mass to form active-containing cylindrical rods known as extrudates; (3) spheronizing the extrudates to form pellets and (4) drying the pellets.
  • the dried pellets can optionally be coated with a lubricant and/or flavoranl, e.g. stearic acid and flavorant.
  • the process can. include moistening a powder mixture of API and excipients, forming extrudates through extrusion, breaking and rounding foe extrudates to round pellets through spheronization, and drying the finished pellets.
  • the pellets can haw sizes in a range of 200 umto2 mm in diameter, for example.
  • the aqueous-based formulation used to form foe wet-extrudable mass can include a considerable percentage of water (wt/wt). The percentage of water can be in a range of 10 wl.% to 90 wt.%, or at least 35 wt.%.
  • Granules produced by this process (aqueous versus non -aqueous) have foe requisite strength and integrity to provide workable, extrudablc and functional spheronized pellets.
  • the pellets can also be referred to as beads or spheroids.
  • the formulation is formed by granulating a mixture of the API with a material (e.g water-insoluble polymer) and one or more other optional excipients, and optionally tailoring the formulation process to a desired particle size range, e.g via extrusion parameters, and/or optionally in combination with one or more steps including sieving, fractional sieving and milling
  • the formulation can be formed by extrusion and spheronization of a mixture of the active compound with one or more other excipients.
  • the extruder can be fitted with an extrusion screen of a desired size, e.g 0.1 mm to 5mm. or 0.5 mm to 2mm.
  • temozolomide can be added to a pre-mixed blend of Ay excipients in a dispensing step, and then a binder solution can be added to prepare a wet mass for extrusion.
  • the drying can be done by tray drying, vacuum drying or fluid bed drying, for example.
  • a sequential method of making approach is described in Table 3 below. U would be understood by the skilled artisan that this sequence is representative and not limiting
  • the dose can be escalated in no more than a 10% dose increase per cycle, based on capsule size with no dose greater than 200mg/m 2 .
  • 150 mg/m 2 is the maximum tolerated dose (MTD) described in the literature so far. Dose increments are 10mg/m 2 .
  • the capsules can include 5, 20, or 100 mg of temozolomide.
  • Early treatment or intervention is also critical in this disease and diagnostic assays measuring the expression of hemangiosarcoma markers coupled with chemotherapeutic intervention is one aspect of the present invention. Such diagnostic markers are disclosed in, for example, U.S. Pat. No. 7,910,315.
  • a formulation having a particle size limit of 2.8 mm or less can be packaged with instructions for enteral feeding tube administration.
  • Examples 1.1 to 1.4 comprising immediate release pellets were made by extrusion- spheronization using the excipients identified in Table 1. Temozolomide was mixed with diluent, a superdisintigrant and spheronizing aids. A wet extrudable mass was prepared, extruded, and 3 above.
  • the extruder was a Caleva bench-top screen Extruder 20 having a screen size of lmm and operated at a speed of about 30-35 RPM.
  • the spheronizer was a Caleva MultiBowl Spheronizer/mbs 250, operating at about 750 - 1500 RPM.
  • the sieves used for fractionation were 1.4 mm, 1.0 mm, 400pm and 250pm.
  • pellets which were retained on the 400pm and 1000pm sieves, thus the mean diameter of pellets in each of the batches was in the region of 400- 1000pm. All pellets assayed to at least 93% of the expected API and showed satisfactory flow-properties, friability and acceptable levels of related substances impurities.
  • the pellets contained about 4 to 6 wt.% or less water by loss on drying.

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  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
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Abstract

L'invention concerne des formes posologiques multiparticulaires à libération immédiate, et des procédés de fabrication et d'utilisation de celles-ci. Les formes posologiques sont destinées à des formulations anticancéreuses appropriées pour des personnes et des animaux.
PCT/US2021/048184 2020-09-30 2021-08-30 Formes posologiques à libération immédiate, procédés de fabrication et d'utilisation de celles-ci WO2022072099A1 (fr)

Applications Claiming Priority (2)

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US202063085402P 2020-09-30 2020-09-30
US63/085,402 2020-09-30

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WO2022072099A1 WO2022072099A1 (fr) 2022-04-07
WO2022072099A9 true WO2022072099A9 (fr) 2022-07-21

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006031524A2 (fr) 2004-09-10 2006-03-23 The Regents Of The Unversity Of Colorado Detection precoce de l'hemangiosarcome et de l'angiosarcome
JP5349290B2 (ja) * 2006-04-03 2013-11-20 オディディ，イサ 薬物送達組成物およびそれを含む医薬品、ならびにその製造方法
WO2010017056A1 (fr) * 2008-08-07 2010-02-11 Merck & Co., Inc. Formulations solides administrées par voie orale contenant un médicament hydrophobe et du tpgs
KR20140087846A (ko) * 2012-12-31 2014-07-09 주식회사 삼양바이오팜 테모졸로미드를 포함하는 안정성이 개선된 약제학적 조성물 및 이의 제조방법
US10709715B2 (en) * 2017-12-03 2020-07-14 Cipla Limited Method of treating hypertension

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